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Editorial

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5 pages, 226 KiB

Open AccessEditorial

Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities

by Antonio Musarò

Cells 2020, 9(9), 2033; https://doi.org/10.3390/cells9092033 - 4 Sep 2020

Cited by 12 | Viewed by 3240

Abstract

The capacity of adult muscle to regenerate in response to injury stimuli represents an important homeostatic process. Regeneration is a highly coordinated program that partially recapitulates the embryonic developmental program and involves the activation of the muscle compartment of stem cells, namely satellite [...] Read more.

The capacity of adult muscle to regenerate in response to injury stimuli represents an important homeostatic process. Regeneration is a highly coordinated program that partially recapitulates the embryonic developmental program and involves the activation of the muscle compartment of stem cells, namely satellite cells, as well as other precursor cells, whose activity is strictly dependent on environmental signals. However, muscle regeneration is severely compromised in several pathological conditions due to either the progressive loss of stem cell populations or to missing signals that limit the damaged tissues from efficiently activating a regenerative program. It is, therefore, plausible that the loss of control over these cells’ fate might lead to pathological cell differentiation, limiting the ability of a pathological muscle to sustain an efficient regenerative process. This Special Issue aims to bring together a collection of original research and review articles addressing the intriguing field of the cellular and molecular players involved in muscle homeostasis and regeneration and to suggest potential therapeutic approaches for degenerating muscle disease. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

Research

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17 pages, 12607 KiB

Open AccessArticle

High-Dimensional Single-Cell Quantitative Profiling of Skeletal Muscle Cell Population Dynamics during Regeneration

by Lucia Lisa Petrilli, Filomena Spada, Alessandro Palma, Alessio Reggio, Marco Rosina, Cesare Gargioli, Luisa Castagnoli, Claudia Fuoco and Gianni Cesareni

Cells 2020, 9(7), 1723; https://doi.org/10.3390/cells9071723 - 18 Jul 2020

Cited by 20 | Viewed by 5253

Abstract

The interstitial space surrounding the skeletal muscle fibers is populated by a variety of mononuclear cell types. Upon acute or chronic insult, these cell populations become activated and initiate finely-orchestrated crosstalk that promotes myofiber repair and regeneration. Mass cytometry is a powerful and [...] Read more.

The interstitial space surrounding the skeletal muscle fibers is populated by a variety of mononuclear cell types. Upon acute or chronic insult, these cell populations become activated and initiate finely-orchestrated crosstalk that promotes myofiber repair and regeneration. Mass cytometry is a powerful and highly multiplexed technique for profiling single-cells. Herein, it was used to dissect the dynamics of cell populations in the skeletal muscle in physiological and pathological conditions. Here, we characterized an antibody panel that could be used to identify most of the cell populations in the muscle interstitial space. By exploiting the mass cytometry resolution, we provided a comprehensive picture of the dynamics of the major cell populations that sensed and responded to acute damage in wild type mice and in a mouse model of Duchenne muscular dystrophy. In addition, we revealed the intrinsic heterogeneity of many of these cell populations. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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21 pages, 3542 KiB

Open AccessArticle

Extracellular Vesicles from Skeletal Muscle Cells Efficiently Promote Myogenesis in Induced Pluripotent Stem Cells

by Denisa Baci, Maila Chirivì, Valentina Pace, Fabio Maiullari, Marika Milan, Andrea Rampin, Paolo Somma, Dario Presutti, Silvia Garavelli, Antonino Bruno, Stefano Cannata, Chiara Lanzuolo, Cesare Gargioli, Roberto Rizzi and Claudia Bearzi

Cells 2020, 9(6), 1527; https://doi.org/10.3390/cells9061527 - 23 Jun 2020

Cited by 18 | Viewed by 5725

Abstract

The recent advances, offered by cell therapy in the regenerative medicine field, offer a revolutionary potential for the development of innovative cures to restore compromised physiological functions or organs. Adult myogenic precursors, such as myoblasts or satellite cells, possess a marked regenerative capacity, [...] Read more.

The recent advances, offered by cell therapy in the regenerative medicine field, offer a revolutionary potential for the development of innovative cures to restore compromised physiological functions or organs. Adult myogenic precursors, such as myoblasts or satellite cells, possess a marked regenerative capacity, but the exploitation of this potential still encounters significant challenges in clinical application, due to low rate of proliferation in vitro, as well as a reduced self-renewal capacity. In this scenario, induced pluripotent stem cells (iPSCs) can offer not only an inexhaustible source of cells for regenerative therapeutic approaches, but also a valuable alternative for in vitro modeling of patient-specific diseases. In this study we established a reliable protocol to induce the myogenic differentiation of iPSCs, generated from pericytes and fibroblasts, exploiting skeletal muscle-derived extracellular vesicles (EVs), in combination with chemically defined factors. This genetic integration-free approach generates functional skeletal myotubes maintaining the engraftment ability in vivo. Our results demonstrate evidence that EVs can act as biological “shuttles” to deliver specific bioactive molecules for a successful transgene-free differentiation offering new opportunities for disease modeling and regenerative approaches. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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18 pages, 3148 KiB

Open AccessArticle

Parkin Overexpression Attenuates Sepsis-Induced Muscle Wasting

by Jean-Philippe Leduc-Gaudet, Dominique Mayaki, Olivier Reynaud, Felipe E. Broering, Tomer J. Chaffer, Sabah N. A. Hussain and Gilles Gouspillou

Cells 2020, 9(6), 1454; https://doi.org/10.3390/cells9061454 - 11 Jun 2020

Cited by 30 | Viewed by 5438

Abstract

Sepsis elicits skeletal muscle weakness and fiber atrophy. The accumulation of injured mitochondria and depressed mitochondrial functions are considered as important triggers of sepsis-induced muscle atrophy. It is unclear whether mitochondrial dysfunctions in septic muscles are due to the inadequate activation of quality [...] Read more.

Sepsis elicits skeletal muscle weakness and fiber atrophy. The accumulation of injured mitochondria and depressed mitochondrial functions are considered as important triggers of sepsis-induced muscle atrophy. It is unclear whether mitochondrial dysfunctions in septic muscles are due to the inadequate activation of quality control processes. We hypothesized that overexpressing Parkin, a protein responsible for the recycling of dysfunctional mitochondria by the autophagy pathway (mitophagy), would confer protection against sepsis-induced muscle atrophy by improving mitochondrial quality and content. Parkin was overexpressed for four weeks in the limb muscles of four-week old mice using intramuscular injections of adeno-associated viruses (AAVs). The cecal ligation and perforation (CLP) procedure was used to induce sepsis. Sham operated animals were used as controls. All animals were studied for 48 h post CLP. Sepsis resulted in major body weight loss and myofiber atrophy. Parkin overexpression prevented myofiber atrophy in CLP mice. Quantitative two-dimensional transmission electron microscopy revealed that sepsis is associated with the accumulation of enlarged and complex mitochondria, an effect which was attenuated by Parkin overexpression. Parkin overexpression also prevented a sepsis-induced decrease in the content of mitochondrial subunits of NADH dehydrogenase and cytochrome C oxidase. We conclude that Parkin overexpression prevents sepsis-induced skeletal muscle atrophy, likely by improving mitochondrial quality and contents. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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29 pages, 5057 KiB

Open AccessArticle

Platelet-Rich Plasma Modulates Gap Junction Functionality and Connexin 43 and 26 Expression During TGF-β1–Induced Fibroblast to Myofibroblast Transition: Clues for Counteracting Fibrosis

by Roberta Squecco, Flaminia Chellini, Eglantina Idrizaj, Alessia Tani, Rachele Garella, Sofia Pancani, Paola Pavan, Franco Bambi, Sandra Zecchi-Orlandini and Chiara Sassoli

Cells 2020, 9(5), 1199; https://doi.org/10.3390/cells9051199 - 12 May 2020

Cited by 23 | Viewed by 3670

Abstract

Skeletal muscle repair/regeneration may benefit by Platelet-Rich Plasma (PRP) treatment owing to PRP pro-myogenic and anti-fibrotic effects. However, PRP anti-fibrotic action remains controversial. Here, we extended our previous researches on the inhibitory effects of PRP on in vitro transforming growth factor (TGF)-β1-induced differentiation [...] Read more.

Skeletal muscle repair/regeneration may benefit by Platelet-Rich Plasma (PRP) treatment owing to PRP pro-myogenic and anti-fibrotic effects. However, PRP anti-fibrotic action remains controversial. Here, we extended our previous researches on the inhibitory effects of PRP on in vitro transforming growth factor (TGF)-β1-induced differentiation of fibroblasts into myofibroblasts, the effector cells of fibrosis, focusing on gap junction (GJ) intercellular communication. The myofibroblastic phenotype was evaluated by cell shape analysis, confocal fluorescence microscopy and Western blotting analyses of α-smooth muscle actin and type-1 collagen expression, and electrophysiological recordings of resting membrane potential, resistance, and capacitance. PRP negatively regulated myofibroblast differentiation by modifying all the assessed parameters. Notably, myofibroblast pairs showed an increase of voltage-dependent GJ functionality paralleled by connexin (Cx) 43 expression increase. TGF-β1-treated cells, when exposed to a GJ blocker, or silenced for Cx43 expression, failed to differentiate towards myofibroblasts. Although a minority, myofibroblast pairs also showed not-voltage-dependent GJ currents and coherently Cx26 expression. PRP abolished the TGF-β1-induced voltage-dependent GJ current appearance while preventing Cx43 increase and promoting Cx26 expression. This study adds insights into molecular and functional mechanisms regulating fibroblast-myofibroblast transition and supports the anti-fibrotic potential of PRP, demonstrating the ability of this product to hamper myofibroblast generation targeting GJs. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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8 pages, 1779 KiB

Open AccessArticle

Satellite Cells in Skeletal Muscle of the Hibernating Dormouse, a Natural Model of Quiescence and Re-Activation: Focus on the Cell Nucleus

by Manuela Malatesta, Manuela Costanzo, Barbara Cisterna and Carlo Zancanaro

Cells 2020, 9(4), 1050; https://doi.org/10.3390/cells9041050 - 23 Apr 2020

Cited by 5 | Viewed by 3310

Abstract

Satellite cells (SCs) participate in skeletal muscle plasticity/regeneration. Activation of SCs implies that nuclear changes underpin a new functional status. In hibernating mammals, periods of reduced metabolic activity alternate with arousals and resumption of bodily functions, thereby leading to repeated cell deactivation and [...] Read more.

Satellite cells (SCs) participate in skeletal muscle plasticity/regeneration. Activation of SCs implies that nuclear changes underpin a new functional status. In hibernating mammals, periods of reduced metabolic activity alternate with arousals and resumption of bodily functions, thereby leading to repeated cell deactivation and reactivation. In hibernation, muscle fibers are preserved despite long periods of immobilization. The structural and functional characteristics of SC nuclei during hibernation have not been investigated yet. Using ultrastructural and immunocytochemical analysis, we found that the SCs of the hibernating edible dormouse, Glis glis, did not show apoptosis or necrosis. Moreover, their nuclei were typical of quiescent cells, showing similar amounts and distributions of heterochromatin, pre-mRNA transcription and processing factors, as well as paired box protein 7 (Pax7) and the myogenic differentiation transcription factor D (MyoD), as in euthermia. However, the finding of accumulated perichromatin granules (i.e., sites of storage/transport of spliced pre-mRNA) in SC nuclei of hibernating dormice suggested slowing down of the nucleus-to-cytoplasm transport. We conclude that during hibernation, SC nuclei maintain similar transcription and splicing activity as in euthermia, indicating an unmodified status during immobilization and hypometabolism. Skeletal muscle preservation during hibernation is presumably not due to SC activation, but rather to the maintenance of some functional activity in myofibers that is able to counteract muscle wasting. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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12 pages, 1864 KiB

Open AccessArticle

Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature

by Anna Picca, Raffaella Beli, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Roberto Bernabei, Cecilia Bucci, Flora Guerra and Emanuele Marzetti

Cells 2020, 9(4), 973; https://doi.org/10.3390/cells9040973 - 15 Apr 2020

Cited by 54 | Viewed by 4909

Abstract

Mitochondrial dysfunction and systemic inflammation are major factors in the development of sarcopenia, but the molecular determinants linking the two mechanisms are only partially understood. The study of extracellular vesicle (EV) trafficking may provide insights into this relationship. Circulating small EVs (sEVs) from [...] Read more.

Mitochondrial dysfunction and systemic inflammation are major factors in the development of sarcopenia, but the molecular determinants linking the two mechanisms are only partially understood. The study of extracellular vesicle (EV) trafficking may provide insights into this relationship. Circulating small EVs (sEVs) from serum of 11 older adults with physical frailty and sarcopenia (PF&S) and 10 controls were purified and characterized. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers, including adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2) were quantified by Western immunoblotting. Participants with PF&S showed higher levels of circulating sEVs relative to controls. Protein levels of CD9 and CD63 were lower in the sEV fraction of PF&S older adults, while CD81 was unvaried between groups. In addition, circulating sEVs from PF&S participants had lower amounts of ATP5A, NDUFS3, and SDHB. No signal was detected for MTCOI, NDUFB8, or UQCRC2 in either participant group. Our findings indicate that, in spite of increased sEV secretion, lower amounts of mitochondrial components are discarded through EV in older adults with PF&S. In-depth analysis of EV trafficking might open new venues for biomarker discovery and treatment development for PF&S. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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16 pages, 3342 KiB

Open AccessArticle

Key Components of Human Myofibre Denervation and Neuromuscular Junction Stability are Modulated by Age and Exercise

by Casper Soendenbroe, Cecilie J. L. Bechshøft, Mette F. Heisterberg, Simon M. Jensen, Emma Bomme, Peter Schjerling, Anders Karlsen, Michael Kjaer, Jesper L. Andersen and Abigail L. Mackey

Cells 2020, 9(4), 893; https://doi.org/10.3390/cells9040893 - 6 Apr 2020

Cited by 33 | Viewed by 5710

Abstract

The decline in muscle mass and function with age is partly caused by a loss of muscle fibres through denervation. The purpose of this study was to investigate the potential of exercise to influence molecular targets involved in neuromuscular junction (NMJ) stability in [...] Read more.

The decline in muscle mass and function with age is partly caused by a loss of muscle fibres through denervation. The purpose of this study was to investigate the potential of exercise to influence molecular targets involved in neuromuscular junction (NMJ) stability in healthy elderly individuals. Participants from two studies (one group of 12 young and 12 elderly females and another group of 25 elderly males) performed a unilateral bout of resistance exercise. Muscle biopsies were collected at 4.5 h and up to 7 days post exercise for tissue analysis and cell culture. Molecular targets related to denervation and NMJ stability were analysed by immunohistochemistry and real-time reverse transcription polymerase chain reaction. In addition to a greater presence of denervated fibres, the muscle samples and cultured myotubes from the elderly individuals displayed altered gene expression levels of acetylcholine receptor (AChR) subunits. A single bout of exercise induced general changes in AChR subunit gene expression within the biopsy sampling timeframe, suggesting a sustained plasticity of the NMJ in elderly individuals. These data support the role of exercise in maintaining NMJ stability, even in elderly inactive individuals. Furthermore, the cell culture findings suggest that the transcriptional capacity of satellite cells for AChR subunit genes is negatively affected by ageing. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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21 pages, 6371 KiB

Open AccessArticle

The Switch from NF-YAl to NF-YAs Isoform Impairs Myotubes Formation

by Debora Libetti, Andrea Bernardini, Sarah Sertic, Graziella Messina, Diletta Dolfini and Roberto Mantovani

Cells 2020, 9(3), 789; https://doi.org/10.3390/cells9030789 - 24 Mar 2020

Cited by 11 | Viewed by 3903

Abstract

NF-YA, the regulatory subunit of the trimeric transcription factor (TF) NF-Y, is regulated by alternative splicing (AS) generating two major isoforms, “long” (NF-YAl) and “short” (NF-YAs). Muscle cells express NF-YAl. We ablated exon 3 in mouse C2C12 cells by a four-guide CRISPR/Cas9n strategy, [...] Read more.

NF-YA, the regulatory subunit of the trimeric transcription factor (TF) NF-Y, is regulated by alternative splicing (AS) generating two major isoforms, “long” (NF-YAl) and “short” (NF-YAs). Muscle cells express NF-YAl. We ablated exon 3 in mouse C2C12 cells by a four-guide CRISPR/Cas9n strategy, obtaining clones expressing exclusively NF-YAs (C2-YAl-KO). C2-YAl-KO cells grow normally, but are unable to differentiate. Myogenin and—to a lesser extent, MyoD— levels are substantially lower in C2-YAl-KO, before and after differentiation. Expression of the fusogenic Myomaker and Myomixer genes, crucial for the early phases of the process, is not induced. Myomaker and Myomixer promoters are bound by MyoD and Myogenin, and Myogenin overexpression induces their expression in C2-YAl-KO. NF-Y inactivation reduces MyoD and Myogenin, but not directly: the Myogenin promoter is CCAAT-less, and the canonical CCAAT of the MyoD promoter is not bound by NF-Y in vivo. We propose that NF-YAl, but not NF-YAs, maintains muscle commitment by indirectly regulating Myogenin and MyoD expression in C2C12 cells. These experiments are the first genetic evidence that the two NF-YA isoforms have functionally distinct roles. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 5912 KiB

Open AccessArticle

The Transcription Factor Nfix Requires RhoA-ROCK1 Dependent Phagocytosis to Mediate Macrophage Skewing during Skeletal Muscle Regeneration

by Marielle Saclier, Michela Lapi, Chiara Bonfanti, Giuliana Rossi, Stefania Antonini and Graziella Messina

Cells 2020, 9(3), 708; https://doi.org/10.3390/cells9030708 - 13 Mar 2020

Cited by 35 | Viewed by 7237

Abstract

Macrophages (MPs) are immune cells which are crucial for tissue repair. In skeletal muscle regeneration, pro-inflammatory cells first infiltrate to promote myogenic cell proliferation, then they switch into an anti-inflammatory phenotype to sustain myogenic cells differentiation and myofiber formation. This phenotypical switch is [...] Read more.

Macrophages (MPs) are immune cells which are crucial for tissue repair. In skeletal muscle regeneration, pro-inflammatory cells first infiltrate to promote myogenic cell proliferation, then they switch into an anti-inflammatory phenotype to sustain myogenic cells differentiation and myofiber formation. This phenotypical switch is induced by dead cell phagocytosis. We previously demonstrated that the transcription factor Nfix, a member of the nuclear factor I (Nfi) family, plays a pivotal role during muscle development, regeneration and in the progression of muscular dystrophies. Here, we show that Nfix is mainly expressed by anti-inflammatory macrophages. Upon acute injury, mice deleted for Nfix in myeloid line displayed a significant defect in the process of muscle regeneration. Indeed, Nfix is involved in the macrophage phenotypical switch and macrophages lacking Nfix failed to adopt an anti-inflammatory phenotype and interact with myogenic cells. Moreover, we demonstrated that phagocytosis induced by the inhibition of the RhoA-ROCK1 pathway leads to Nfix expression and, consequently, to acquisition of the anti-inflammatory phenotype. Our study identified Nfix as a link between RhoA-ROCK1-dependent phagocytosis and the MP phenotypical switch, thus establishing a new role for Nfix in macrophage biology for the resolution of inflammation and tissue repair. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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21 pages, 3648 KiB

Open AccessArticle

TGF-β Regulates Collagen Type I Expression in Myoblasts and Myotubes via Transient Ctgf and Fgf-2 Expression

by Michèle M. G. Hillege, Ricardo A. Galli Caro, Carla Offringa, Gerard M. J. de Wit, Richard T. Jaspers and Willem M. H. Hoogaars

Cells 2020, 9(2), 375; https://doi.org/10.3390/cells9020375 - 6 Feb 2020

Cited by 49 | Viewed by 10987

Abstract

Transforming Growth Factor β (TGF-β) is involved in fibrosis as well as the regulation of muscle mass, and contributes to the progressive pathology of muscle wasting disorders. However, little is known regarding the time-dependent signalling of TGF-β in myoblasts and myotubes, as well [...] Read more.

Transforming Growth Factor β (TGF-β) is involved in fibrosis as well as the regulation of muscle mass, and contributes to the progressive pathology of muscle wasting disorders. However, little is known regarding the time-dependent signalling of TGF-β in myoblasts and myotubes, as well as how TGF-β affects collagen type I expression and the phenotypes of these cells. Here, we assessed effects of TGF-β on gene expression in C2C12 myoblasts and myotubes after 1, 3, 9, 24 and 48 h treatment. In myoblasts, various myogenic genes were repressed after 9, 24 and 48 h, while in myotubes only a reduction in Myh3 expression was observed. In both myoblasts and myotubes, TGF-β acutely induced the expression of a subset of genes involved in fibrosis, such as Ctgf and Fgf-2, which was subsequently followed by increased expression of Col1a1. Knockdown of Ctgf and Fgf-2 resulted in a lower Col1a1 expression level. Furthermore, the effects of TGF-β on myogenic and fibrotic gene expression were more pronounced than those of myostatin, and knockdown of TGF-β type I receptor Tgfbr1, but not receptor Acvr1b, resulted in a reduction in Ctgf and Col1a1 expression. These results indicate that, during muscle regeneration, TGF-β induces fibrosis via Tgfbr1 by stimulating the autocrine signalling of Ctgf and Fgf-2. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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22 pages, 10012 KiB

Open AccessArticle

Priority Strategy of Intracellular Ca²⁺ Homeostasis in Skeletal Muscle Fibers during the Multiple Stresses of Hibernation

by Jie Zhang, Xiaoyu Li, Fazeela Ismail, Shenhui Xu, Zhe Wang, Xin Peng, Chenxi Yang, Hui Chang, Huiping Wang and Yunfang Gao

Cells 2020, 9(1), 42; https://doi.org/10.3390/cells9010042 - 22 Dec 2019

Cited by 16 | Viewed by 3828

Abstract

Intracellular calcium (Ca²⁺) homeostasis plays a vital role in the preservation of skeletal muscle. In view of the well-maintained skeletal muscle found in Daurian ground squirrels (Spermophilus dauricus) during hibernation, we hypothesized that hibernators possess unique strategies of intracellular [...] Read more.

Intracellular calcium (Ca²⁺) homeostasis plays a vital role in the preservation of skeletal muscle. In view of the well-maintained skeletal muscle found in Daurian ground squirrels (Spermophilus dauricus) during hibernation, we hypothesized that hibernators possess unique strategies of intracellular Ca²⁺ homeostasis. Here, cytoplasmic, sarcoplasmic reticulum (SR), and mitochondrial Ca²⁺ levels, as well as the potential Ca²⁺ regulatory mechanisms, were investigated in skeletal muscle fibers of Daurian ground squirrels at different stages of hibernation. The results showed that cytoplasmic Ca²⁺ levels increased in the skeletal muscle fibers during late torpor (LT) and inter-bout arousal (IBA), and partially recovered when the animals re-entered torpor (early torpor, ET). Furthermore, compared with levels in the summer active or pre-hibernation state, the activity and protein expression levels of six major Ca²⁺ channels/proteins were up-regulated during hibernation, including the store-operated Ca²⁺ entry (SOCE), ryanodine receptor 1 (RyR1), leucine zipper-EF-hand containing transmembrane protein 1 (LETM1), SR Ca²⁺ ATPase 1 (SERCA1), mitochondrial calcium uniporter complex (MCU complex), and calmodulin (CALM). Among these, the increased extracellular Ca²⁺ influx mediated by SOCE, SR Ca²⁺ release mediated by RyR1, and mitochondrial Ca²⁺ extrusion mediated by LETM1 may be triggers for the periodic elevation in cytoplasmic Ca²⁺ levels observed during hibernation. Furthermore, the increased SR Ca²⁺ uptake through SERCA1, mitochondrial Ca²⁺ uptake induced by MCU, and elevated free Ca²⁺ binding capacity mediated by CALM may be vital strategies in hibernating ground squirrels to attenuate cytoplasmic Ca²⁺ levels and restore Ca²⁺ homeostasis during hibernation. Compared with that in LT or IBA, the decreased extracellular Ca²⁺ influx mediated by SOCE and elevated mitochondrial Ca²⁺ uptake induced by MCU may be important mechanisms for the partial cytoplasmic Ca²⁺ recovery in ET. Overall, under extreme conditions, hibernating ground squirrels still possess the ability to maintain intracellular Ca²⁺ homeostasis. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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26 pages, 17177 KiB

Open AccessArticle

Transthyretin Maintains Muscle Homeostasis through the Novel Shuttle Pathway of Thyroid Hormones during Myoblast Differentiation

by Eun Ju Lee, Sibhghatulla Shaikh, Dukhwan Choi, Khurshid Ahmad, Mohammad Hassan Baig, Jeong Ho Lim, Yong-Ho Lee, Sang Joon Park, Yong-Woon Kim, So-Young Park and Inho Choi

Cells 2019, 8(12), 1565; https://doi.org/10.3390/cells8121565 - 4 Dec 2019

Cited by 15 | Viewed by 5075

Abstract

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- [...] Read more.

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T₄) complex, which consecutively induces the intracellular triiodothyronine (T₃) level, followed by T₃ secretion out of the cell through the exosomes. The decrease in T₃ with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T₃-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXRγ (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T₄, skeletal muscle also distributes generated T₃ to other tissues and has a vital role in sensing the intracellular T₄ level. Furthermore, the results of TTR function with T₄ in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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17 pages, 4036 KiB

Open AccessArticle

mTORC1 Mediates Lysine-Induced Satellite Cell Activation to Promote Skeletal Muscle Growth

by Cheng-long Jin, Jin-ling Ye, Jinzeng Yang, Chun-qi Gao, Hui-chao Yan, Hai-chang Li and Xiu-qi Wang

Cells 2019, 8(12), 1549; https://doi.org/10.3390/cells8121549 - 30 Nov 2019

Cited by 41 | Viewed by 5728

Abstract

As the first limiting amino acid, lysine (Lys) has been thought to promote muscle fiber hypertrophy by increasing protein synthesis. However, the functions of Lys seem far more complex than that. Despite the fact that satellite cells (SCs) play an important role in [...] Read more.

As the first limiting amino acid, lysine (Lys) has been thought to promote muscle fiber hypertrophy by increasing protein synthesis. However, the functions of Lys seem far more complex than that. Despite the fact that satellite cells (SCs) play an important role in skeletal muscle growth, the communication between Lys and SCs remains unclear. In this study, we investigated whether SCs participate directly in Lys-induced skeletal muscle growth and whether the mammalian target of rapamycin complex 1 (mTORC1) pathway was activated both in vivo and in vitro to mediate SC functions in response to Lys supplementation. Subsequently, the skeletal muscle growth of piglets was controlled by dietary Lys supplementation. Isobaric tag for relative and absolute quantitation (iTRAQ) analysis showed activated SCs were required for longissimus dorsi muscle growth, and this effect was accompanied by mTORC1 pathway upregulation. Furthermore, SC proliferation was governed by medium Lys concentrations, and the mTORC1 pathway was significantly enhanced in vitro. After verifying that rapamycin inhibits the mTORC1 pathway and suppresses SC proliferation, we conclude that Lys is not only a molecular building block for protein synthesis but also a signal that activates SCs to manipulate muscle growth via the mTORC1 pathway. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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Review

Jump to: Editorial, Research

21 pages, 741 KiB

Open AccessReview

The Impact of Glucose-Lowering Drugs on Sarcopenia in Type 2 Diabetes: Current Evidence and Underlying Mechanisms

by Elena Massimino, Anna Izzo, Gabriele Riccardi and Giuseppe Della Pepa

Cells 2021, 10(8), 1958; https://doi.org/10.3390/cells10081958 - 1 Aug 2021

Cited by 46 | Viewed by 10999

Abstract

The age-related decrease in skeletal muscle mass together with the loss of muscle power and function is defined sarcopenia. Mounting evidence suggests that the prevalence of sarcopenia is higher in patients with type 2 diabetes mellitus (T2DM), and different mechanisms may be responsible [...] Read more.

The age-related decrease in skeletal muscle mass together with the loss of muscle power and function is defined sarcopenia. Mounting evidence suggests that the prevalence of sarcopenia is higher in patients with type 2 diabetes mellitus (T2DM), and different mechanisms may be responsible for this association such as impaired insulin sensitivity, chronic hyperglycemia, advanced glycosylation end products, subclinical inflammation, microvascular and macrovascular complications. Glucose-lowering drugs prescribed for patients with T2DM might impact on these mechanisms leading to harmful or beneficial effect on skeletal muscle. Importantly, beyond their glucose-lowering effects, glucose-lowering drugs may affect per se the equilibrium between protein anabolism and catabolism through several mechanisms involved in skeletal muscle physiology, contributing to sarcopenia. The aim of this narrative review is to provide an update on the effects of glucose-lowering drugs on sarcopenia in individuals with T2DM, focusing on the parameters used to define sarcopenia: muscle strength (evaluated by handgrip strength), muscle quantity/quality (evaluated by appendicular lean mass or skeletal muscle mass and their indexes), and physical performance (evaluated by gait speed or short physical performance battery). Furthermore, we also describe the plausible mechanisms by which glucose-lowering drugs may impact on sarcopenia. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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41 pages, 2344 KiB

Open AccessReview

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

by Lorenzo Maggi, Silvia Bonanno, Concetta Altamura and Jean-François Desaphy

Cells 2021, 10(6), 1521; https://doi.org/10.3390/cells10061521 - 16 Jun 2021

Cited by 28 | Viewed by 8945

Abstract

Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development [...] Read more.

Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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35 pages, 2197 KiB

Open AccessReview

The Diversity of Muscles and Their Regenerative Potential across Animals

by Letizia Zullo, Matteo Bozzo, Alon Daya, Alessio Di Clemente, Francesco Paolo Mancini, Aram Megighian, Nir Nesher, Eric Röttinger, Tal Shomrat, Stefano Tiozzo, Alberto Zullo and Simona Candiani

Cells 2020, 9(9), 1925; https://doi.org/10.3390/cells9091925 - 19 Aug 2020

Cited by 10 | Viewed by 6476

Abstract

Cells with contractile functions are present in almost all metazoans, and so are the related processes of muscle homeostasis and regeneration. Regeneration itself is a complex process unevenly spread across metazoans that ranges from full-body regeneration to partial reconstruction of damaged organs or [...] Read more.

Cells with contractile functions are present in almost all metazoans, and so are the related processes of muscle homeostasis and regeneration. Regeneration itself is a complex process unevenly spread across metazoans that ranges from full-body regeneration to partial reconstruction of damaged organs or body tissues, including muscles. The cellular and molecular mechanisms involved in regenerative processes can be homologous, co-opted, and/or evolved independently. By comparing the mechanisms of muscle homeostasis and regeneration throughout the diversity of animal body-plans and life cycles, it is possible to identify conserved and divergent cellular and molecular mechanisms underlying muscle plasticity. In this review we aim at providing an overview of muscle regeneration studies in metazoans, highlighting the major regenerative strategies and molecular pathways involved. By gathering these findings, we wish to advocate a comparative and evolutionary approach to prompt a wider use of “non-canonical” animal models for molecular and even pharmacological studies in the field of muscle regeneration. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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26 pages, 964 KiB

Open AccessReview

“The Social Network” and Muscular Dystrophies: The Lesson Learnt about the Niche Environment as a Target for Therapeutic Strategies

by Ornella Cappellari, Paola Mantuano and Annamaria De Luca

Cells 2020, 9(7), 1659; https://doi.org/10.3390/cells9071659 - 9 Jul 2020

Cited by 25 | Viewed by 3561

Abstract

The muscle stem cells niche is essential in neuromuscular disorders. Muscle injury and myofiber death are the main triggers of muscle regeneration via satellite cell activation. However, in degenerative diseases such as muscular dystrophy, regeneration still keep elusive. In these pathologies, stem cell [...] Read more.

The muscle stem cells niche is essential in neuromuscular disorders. Muscle injury and myofiber death are the main triggers of muscle regeneration via satellite cell activation. However, in degenerative diseases such as muscular dystrophy, regeneration still keep elusive. In these pathologies, stem cell loss occurs over time, and missing signals limiting damaged tissue from activating the regenerative process can be envisaged. It is unclear what comes first: the lack of regeneration due to satellite cell defects, their pool exhaustion for degeneration/regeneration cycles, or the inhibitory mechanisms caused by muscle damage and fibrosis mediators. Herein, Duchenne muscular dystrophy has been taken as a paradigm, as several drugs have been tested at the preclinical and clinical levels, targeting secondary events in the complex pathogenesis derived from lack of dystrophin. We focused on the crucial roles that pro-inflammatory and pro-fibrotic cytokines play in triggering muscle necrosis after damage and stimulating satellite cell activation and self-renewal, along with growth and mechanical factors. These processes contribute to regeneration and niche maintenance. We review the main effects of drugs on regeneration biomarkers to assess whether targeting pathogenic events can help to protect niche homeostasis and enhance regeneration efficiency other than protecting newly formed fibers from further damage. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

33 pages, 8920 KiB

Open AccessReview

Identifying the Structural Adaptations that Drive the Mechanical Load-Induced Growth of Skeletal Muscle: A Scoping Review

by Kent W. Jorgenson, Stuart M. Phillips and Troy A. Hornberger

Cells 2020, 9(7), 1658; https://doi.org/10.3390/cells9071658 - 9 Jul 2020

Cited by 78 | Viewed by 30213

Abstract

The maintenance of skeletal muscle mass plays a critical role in health and quality of life. One of the most potent regulators of skeletal muscle mass is mechanical loading, and numerous studies have led to a reasonably clear understanding of the macroscopic and [...] Read more.

The maintenance of skeletal muscle mass plays a critical role in health and quality of life. One of the most potent regulators of skeletal muscle mass is mechanical loading, and numerous studies have led to a reasonably clear understanding of the macroscopic and microscopic changes that occur when the mechanical environment is altered. For instance, an increase in mechanical loading induces a growth response that is mediated, at least in part, by an increase in the cross-sectional area of the myofibers (i.e., myofiber hypertrophy). However, very little is known about the ultrastructural adaptations that drive this response. Even the most basic questions, such as whether mechanical load-induced myofiber hypertrophy is mediated by an increase in the size of the pre-existing myofibrils and/or an increase in the number myofibrils, have not been resolved. In this review, we thoroughly summarize what is currently known about the macroscopic, microscopic and ultrastructural changes that drive mechanical load-induced growth and highlight the critical gaps in knowledge that need to be filled. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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36 pages, 4196 KiB

Open AccessFeature PaperReview

Genetic Control of Muscle Diversification and Homeostasis: Insights from Drosophila

by Preethi Poovathumkadavil and Krzysztof Jagla

Cells 2020, 9(6), 1543; https://doi.org/10.3390/cells9061543 - 25 Jun 2020

Cited by 13 | Viewed by 7107

Abstract

In the fruit fly, Drosophila melanogaster, the larval somatic muscles or the adult thoracic flight and leg muscles are the major voluntary locomotory organs. They share several developmental and structural similarities with vertebrate skeletal muscles. To ensure appropriate activity levels for their [...] Read more.

In the fruit fly, Drosophila melanogaster, the larval somatic muscles or the adult thoracic flight and leg muscles are the major voluntary locomotory organs. They share several developmental and structural similarities with vertebrate skeletal muscles. To ensure appropriate activity levels for their functions such as hatching in the embryo, crawling in the larva, and jumping and flying in adult flies all muscle components need to be maintained in a functionally stable or homeostatic state despite constant strain. This requires that the muscles develop in a coordinated manner with appropriate connections to other cell types they communicate with. Various signaling pathways as well as extrinsic and intrinsic factors are known to play a role during Drosophila muscle development, diversification, and homeostasis. In this review, we discuss genetic control mechanisms of muscle contraction, development, and homeostasis with particular emphasis on the contractile unit of the muscle, the sarcomere. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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24 pages, 1350 KiB

Open AccessReview

The Survey of Cells Responsible for Heterotopic Ossification Development in Skeletal Muscles—Human and Mouse Models

by Łukasz Pulik, Bartosz Mierzejewski, Maria A. Ciemerych, Edyta Brzóska and Paweł Łęgosz

Cells 2020, 9(6), 1324; https://doi.org/10.3390/cells9061324 - 26 May 2020

Cited by 18 | Viewed by 4440

Abstract

Heterotopic ossification (HO) manifests as bone development in the skeletal muscles and surrounding soft tissues. It can be caused by injury, surgery, or may have a genetic background. In each case, its development might differ, and depending on the age, sex, and patient’s [...] Read more.

Heterotopic ossification (HO) manifests as bone development in the skeletal muscles and surrounding soft tissues. It can be caused by injury, surgery, or may have a genetic background. In each case, its development might differ, and depending on the age, sex, and patient’s conditions, it could lead to a more or a less severe outcome. In the case of the injury or surgery provoked ossification development, it could be, to some extent, prevented by treatments. As far as genetic disorders are concerned, such prevention approaches are highly limited. Many lines of evidence point to the inflammatory process and abnormalities in the bone morphogenetic factor signaling pathway as the molecular and cellular backgrounds for HO development. However, the clear targets allowing the design of treatments preventing or lowering HO have not been identified yet. In this review, we summarize current knowledge on HO types, its symptoms, and possible ways of prevention and treatment. We also describe the molecules and cells in which abnormal function could lead to HO development. We emphasize the studies involving animal models of HO as being of great importance for understanding and future designing of the tools to counteract this pathology. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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28 pages, 2924 KiB

Open AccessReview

Mechanisms Regulating Muscle Regeneration: Insights into the Interrelated and Time-Dependent Phases of Tissue Healing

by Laura Forcina, Marianna Cosentino and Antonio Musarò

Cells 2020, 9(5), 1297; https://doi.org/10.3390/cells9051297 - 22 May 2020

Cited by 131 | Viewed by 16524

Abstract

Despite a massive body of knowledge which has been produced related to the mechanisms guiding muscle regeneration, great interest still moves the scientific community toward the study of different aspects of skeletal muscle homeostasis, plasticity, and regeneration. Indeed, the lack of effective therapies [...] Read more.

Despite a massive body of knowledge which has been produced related to the mechanisms guiding muscle regeneration, great interest still moves the scientific community toward the study of different aspects of skeletal muscle homeostasis, plasticity, and regeneration. Indeed, the lack of effective therapies for several physiopathologic conditions suggests that a comprehensive knowledge of the different aspects of cellular behavior and molecular pathways, regulating each regenerative stage, has to be still devised. Hence, it is important to perform even more focused studies, taking the advantage of robust markers, reliable techniques, and reproducible protocols. Here, we provide an overview about the general aspects of muscle regeneration and discuss the different approaches to study the interrelated and time-dependent phases of muscle healing. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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12 pages, 996 KiB

Open AccessReview

Role of Insulin-Like Growth Factor Receptor 2 across Muscle Homeostasis: Implications for Treating Muscular Dystrophy

by Yvan Torrente, Pamela Bella, Luana Tripodi, Chiara Villa and Andrea Farini

Cells 2020, 9(2), 441; https://doi.org/10.3390/cells9020441 - 14 Feb 2020

Cited by 25 | Viewed by 4336

Abstract

The insulin-like growth factor 2 receptor (IGF2R) plays a major role in binding and regulating the circulating and tissue levels of the mitogenic peptide insulin-like growth factor 2 (IGF2). IGF2/IGF2R interaction influences cell growth, survival, and migration in normal tissue development, and the [...] Read more.

The insulin-like growth factor 2 receptor (IGF2R) plays a major role in binding and regulating the circulating and tissue levels of the mitogenic peptide insulin-like growth factor 2 (IGF2). IGF2/IGF2R interaction influences cell growth, survival, and migration in normal tissue development, and the deregulation of IGF2R expression has been associated with growth-related disease and cancer. IGF2R overexpression has been implicated in heart and muscle disease progression. Recent research findings suggest novel approaches to target IGF2R action. This review highlights recent advances in the understanding of the IGF2R structure and pathways related to muscle homeostasis. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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31 pages, 951 KiB

Open AccessReview

Genetic Associations with Aging Muscle: A Systematic Review

by Jedd Pratt, Colin Boreham, Sean Ennis, Anthony W. Ryan and Giuseppe De Vito

Cells 2020, 9(1), 12; https://doi.org/10.3390/cells9010012 - 19 Dec 2019

Cited by 44 | Viewed by 7714

Abstract

The age-related decline in skeletal muscle mass, strength and function known as ‘sarcopenia’ is associated with multiple adverse health outcomes, including cardiovascular disease, stroke, functional disability and mortality. While skeletal muscle properties are known to be highly heritable, evidence regarding the specific genes [...] Read more.

The age-related decline in skeletal muscle mass, strength and function known as ‘sarcopenia’ is associated with multiple adverse health outcomes, including cardiovascular disease, stroke, functional disability and mortality. While skeletal muscle properties are known to be highly heritable, evidence regarding the specific genes underpinning this heritability is currently inconclusive. This review aimed to identify genetic variants known to be associated with muscle phenotypes relevant to sarcopenia. PubMed, Embase and Web of Science were systematically searched (from January 2004 to March 2019) using pre-defined search terms such as “aging”, “sarcopenia”, “skeletal muscle”, “muscle strength” and “genetic association”. Candidate gene association studies and genome wide association studies that examined the genetic association with muscle phenotypes in non-institutionalised adults aged ≥50 years were included. Fifty-four studies were included in the final analysis. Twenty-six genes and 88 DNA polymorphisms were analysed across the 54 studies. The ACTN3, ACE and VDR genes were the most frequently studied, although the IGF1/IGFBP3, TNFα, APOE, CNTF/R and UCP2/3 genes were also shown to be significantly associated with muscle phenotypes in two or more studies. Ten DNA polymorphisms (rs154410, rs2228570, rs1800169, rs3093059, rs1800629, rs1815739, rs1799752, rs7412, rs429358 and 192 bp allele) were significantly associated with muscle phenotypes in two or more studies. Through the identification of key gene variants, this review furthers the elucidation of genetic associations with muscle phenotypes associated with sarcopenia. Full article

(This article belongs to the Special Issue Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities)

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